Multi-capillary electrophoresis cartridge interface mechanism

ABSTRACT

The present invention provides for an interface mechanism in a bio-separation instrument that makes interface connections to a multi-channel cartridge. The interface mechanism precisely positions the cartridge in relation to the support elements in the instrument (e.g., high-voltage, gas pressure, incident radiation and detector), and makes automated, reliable and secured alignments and connections between various components in the cartridge and the support elements in the supporting instrument. The interface mechanism comprises pneumatically or electromechanically driven actuators for engaging support elements in the instrument to components on the cartridge. After the cartridge has been securely received by the interface mechanism, the connection sequence is initiated. The interface provides separate high voltage and optical connections for each separation channel in the cartridge, thus providing channel-to-channel isolation from cross talk both electrically and optically.

This application claims the priority of U.S. Provisional PatentApplication No. 60/462,481, filed on Apr. 11, 2003.

This application is a Continuation-in-Part of U.S. patent applicationSer. No. 10/059,993 entitled “Multi-Channel Bio-Separation Cartridge,”filed on Jan. 28, 2002 now U.S. Pat. No. 7,309,409; and U.S. patentapplication Ser. No. 10/060,052, entitled “Optical Detection In AMulti-Channel Bio-Separation System”, filed on Jan. 28, 2002 now U.S.Pat. No. 6,828,567; and U.S. patent application Ser. No. 10/319,803,entitled “Optical Detection Alignment Coupling Apparatus”, filed on Dec.13, 2002 now U.S. Pat. No. 7,250,099; and PCT Application No.PCT/US03/39971, entitled “Optical Detection Alignment CouplingApparatus”, filed on Dec. 15, 2003; which are commonly assigned toBioCal Technology, Inc., the assignee of the present invention.

The above-mentioned applications, and all other applications, documentsand references noted in the disclosure herein below, are fullyincorporated by reference as if fully set forth herein.

BACKGROUND OF THE INVENTION

The present invention relates to bio-separation, and more particularlyto an interface mechanism in a bio-separation instrument, which supportsthe use and functions of a multi-channel capillary cartridge, inparticular a multi-channel cartridge having multi-separation columnswith integrated reagent reservoir and excitation radiation and detectionoptics.

Bioanalysis, such as DNA analysis, is rapidly making the transition froma purely scientific quest for accuracy to a routine procedure withincreased, proven dependability. Medical researchers, pharmacologists,and forensic investigators all use DNA analysis in the pursuit of theirtasks. Yet due to the complexity of the equipment that detects andmeasures DNA samples and the difficulty in preparing the samples, theexisting DNA analysis procedures are often time-consuming and expensive.It is therefore desirable to reduce the size, number of parts, and costof equipment, to ease sample handling during the process, and ingeneral, to have a simplified, low cost, high sensitivity detector.

One type of DNA analysis instrument separates DNA molecules by relyingon electrophoresis. Electrophoresis techniques could be used to separatefragments of DNA for genotyping applications, including human identitytesting, expression analysis, pathogen detection, mutation detection,and pharmacogenetics studies. The term electrophoresis refers to themovement of a charged molecule under the influence of an electric field.Electrophoresis can be used to separate molecules that have equivalentcharge-to-mass ratios but different masses. DNA fragments are oneexample of such molecules.

There are a variety of commercially available instruments applyingelectrophoresis to analyze DNA samples. One such type is a capillaryelectrophoresis (CE) instrument. By applying electrophoresis in a fusedsilica capillary column carrying a buffer solution, the sample sizerequirement is significantly smaller and the speed of separation andresolution can be increased multiple times compared to the slabgel-electrophoresis method. These DNA fragments in CE are often detectedby directing light through the capillary wall, at the componentsseparating from the sample that has been tagged with a fluorescencematerial, and detecting the fluorescence emissions induced by theincident light. The intensities of the emission are representative ofthe concentration, amount and/or size of the components of the sample.In the past, Laser-induced fluorescence (LIF) detection methods had beendeveloped for CE instruments. Fluorescence detection is often thedetection method of choice in the fields of genomics and proteomicsbecause of its outstanding sensitivity compared to other detectionmethods.

Some of the challenges in designing CE-based instruments relate to thesupport of the capillaries and alignment of the capillaries to supportelements (e.g., excitation and detection optics). Biocal Technology,Inc. developed a CE-based instrument and a multi-channel cartridge foruse therein, which comprises multi-separation columns with integratedreagent reservoir and excitation radiation and detection optics. (TheBiocal cartridge and system are described in U.S. patent applicationSer. No. 10/059,993 and U.S. patent application Ser. No. 10/060,052,which had been incorporated by reference herein). The cartridge isdesigned to be supported by the instrument, with all essential cartridgeelements aligned and coupled to support elements in the instrument. Itis desirable to provide a reliable and secure interfacing mechanism inthe instrument to make such coupling to the cartridge.

SUMMARY OF THE INVENTION

The present invention provides for an interface mechanism in abio-separation instrument that makes interface connections to amulti-channel cartridge. One aspect of the present invention provides aninterface mechanism that precisely positions the cartridge in relationto the support elements (e.g., electrical power such as high-voltage,gas pressure, incident radiation and detection optics) provided by thesupporting instrument, and makes automated, reliable and securedalignments and connections between various components in the cartridgeand the support elements in the instrument. Such alignments andconnections are reliably implemented, in a reliable automated sequence,after the cartridge had been securely received by the interfacemechanism.

In another aspect of the present invention, the interface mechanismcomprises pneumatically or electro-mechanically driven actuators forengaging structures on the cartridge, to securely connect at least oneof gas pressure, high voltage, emission detection optics, and excitationradiation optics. In one embodiment, the pneumatically driven actuatorscomprise gas driven pistons. After the cartridge has been securelyreceived by the interface mechanism, the connection sequence isinitiated. In one embodiment, the connection sequence is initiated by auser. Alternatively, the connection sequence may be initiatedautomatically in response to a secured reception of the cartridge to theinterface mechanism. A disconnection sequence is provided to disconnectthe support elements from the cartridge, allowing the cartridge to besafely removed from the instrument.

In a further aspect of the present invention, the interface providesseparate high voltage and optical connections for each separationchannel in the cartridge, thus providing channel-to-channel isolationfrom cross talk both electrically and optically.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and advantages of theinvention, as well as the preferred mode of use, reference should bemade to the following detailed description read in conjunction with theaccompanying drawings. In the following drawings, like referencenumerals designate like or similar parts throughout the drawings.

FIG. 1 is a schematic view of a capillary electrophoresis system thatincorporates the present invention.

FIG. 2 is a perspective view of the capillary electrophoresissystem/machine in accordance with one embodiment of the presentinvention.

FIG. 3 is a diagram of the control system.

FIG. 4 is a perspective view of the cartridge lower section withexcitation fibers.

FIG. 5 is a perspective view of the cartridge mid-section and the lowersection with excitation fibers before being joined.

FIG. 6 is a perspective view of the cartridge mid-section and the lowersection with excitation fibers after being joined.

FIG. 7 is a perspective front view of the combined cartridge mid-sectionand the lower section in FIG. 6 with capillaries before being joined.

FIG. 8 is perspective front view of the cartridge mid-section and lowersection with capillaries after being joined.

FIG. 9 is a perspective rear view of the cartridge mid-section and lowersection with the gel reservoir.

FIG. 10 is a perspective front view of the cartridge mid-section andlower section with the gel reservoir and front and rear covers.

FIG. 11 is a front perspective view of the cartridge with detectionoptics contained in a closed housing.

FIG. 12 is a front perspective sectional view of the cartridge in FIG.11 with the excitation and emission optical system.

FIG. 13 is a perspective sectional view of the cartridge with schematicof the detector system.

FIG. 14 is a front perspective sectional view of the cartridge with theexcitation and emission optical system.

FIG. 15 is an enlarged view of section A in FIG. 14 and a perspectivesectional view of the cartridge section A shown in FIG. 13.

FIG. 16 is a perspective sectional view of the cartridge section B shownin FIG. 13.

FIG. 17 is perspective sectional view of the detection zone with lens,probe, capillary, and excitation fiber.

FIG. 18 is a schematic overview illustrating the relationship betweenthe cartridge components and associated components on the interfacemechanism.

FIGS. 19A and 19B show the external structure of a cartridge inaccordance with another embodiment of the present invention.

FIGS. 20 and 21 is a rear perspective view of the interface mechanism inaccordance with one embodiment of the present invention.

FIGS. 22A and 22B are front perspective views of the interfacemechanism.

FIG. 23 is a front view of the interface mechanism.

FIG. 24 is a rear view of the interface mechanism.

FIG. 25 is a side view of the interface mechanism.

FIG. 26 is a side sectional view of the interface mechanism, taken alongline 26-26 in FIG. 28.

FIG. 27 is a bottom view of the interface mechanism.

FIG. 28 is a partial top view and top sectional of the interfacemechanism, taken alone line 28-28 in FIG. 23, to show the top and bottomhalves of the interface mechanism.

FIG. 29 is a rear view of the front support block of the interfacemechanism.

FIG. 30 is a front view of the front support block of the interfacemechanism.

FIG. 31 is a front view of the rear support block of the interfacemechanism.

FIG. 32 is a rear view of the rear support block of the interfacemechanism.

DETAILED DESCRIPTION OF ILLUSTRATED EMBODIMENTS

This invention is described below in reference to various embodimentswith reference to the figures. While this invention is described interms of the best mode for achieving this invention's objectives, itwill be appreciated by those skilled in the art that variations may beaccomplished in view of these teachings without deviating from thespirit or scope of the invention.

The present invention provides for an interface mechanism bio-separationinstrument that supports a multi-segment cartridge. For purpose ofillustrating the principles of the present invention and not bylimitation, the present invention is described by reference toembodiments directed to capillary electrophoresis and radiation inducedfluorescence.

Overview of CE

Referring to FIG. 1, a bio-separation system, more specifically acapillary electrophoresis (CE) system 200 that incorporates the presentinvention is schematically illustrated. The CE system 200 generallycomprises a capillary separation column 22 (e.g., 200-500 μm O.D.),which defines a separation channel 36 (e.g., 25-200 μm I.D.). Thecapillary column 22 may be made of fused silica, glass, polyimide, orother plastic/ceramic/glassy materials. The inside walls of theseparation column 22 (i.e., the walls of the separation channel 36) maybe coated with a material that can build up an electrostatic charge tofacilitate electrophoresis and/or electrokinetic migration of the samplecomponents. The separation channel 36 is filled with a separationsupport medium, which may simply be a running buffer, or a sieving gelmatrix known in the art. For radiation induced fluorescence detection,the gel matrix includes a known fluorophore, such as Ethidium Bromide.

One end of the capillary column 22 is submerged in a reservoir 28 ofrunning buffer/gel 34. The other end of the capillary column 22 iscoupled to the sample vial 26. It is understood that the detectionconfigurations shown in the other embodiments can be equally implementedin a system similar to the CE system 20. Also, the separation channel 36may be one straight capillary or micro-channel with a section of thedetection window closest to the gel-reservoir at the exit end being thedetection zone, which is the current preferred mode of our invention. Aradiation detector 24 is positioned outside a transparent section of thecapillary walls at detection zone 30. An excitation fiber 16 extendsfrom a radiation source 18 (e.g., LED or laser) and is directed at thedetection zone 30 outside the walls of the column. Electrodes 12 and 14,that are part of the cartridge assembly are coupled to the bufferreservoirs 26 and gel reservoir 28 to complete the electrophoresis path.

For the sake of completeness, it is sufficient to briefly mention theoperation of the CE system 200. In operation, a prepared biologicalsample (e.g., a DNA sample), direct from Polymerase Chain Reaction (PCR)machine is introduced into the far end of the capillary column away fromthe detection zone by any of a number of ways that is not part of thepresent invention (e.g., electrokinetic injection from a samplereservoir or physical pressure injection using a syringe pump). Thesample binds to the fluorophore.

When a DC potential (e.g., 1-30 KV) is applied between electrodes 12 and14, the sample migrates under the applied electric potential along theseparation channel 36 (e.g. DNA that is negatively charged travelsthrough the sieving gel with an integrated dye matrix/fluorophore towarda positive electrode as shown in FIG. 1) and separates into bands ofsample components. The extent of separation and distance moved along theseparation channel 36 depends on a number of factors, such as migrationmobility of the sample components, the mass and size or length of thesample components, and the separation support medium. The driving forcesin the separation channel 36 for the separation of samples could beelectrophoretic, pressure, or electro-osmotic flow (EOF) means.

When the sample reaches the detection zone, excitation radiation isdirected via the excitation fiber 16 at the detection zone. The samplecomponents fluoresce with intensities proportional to the concentrationsof the respective sample components (proportional to the amount offluorescent tag material). The detector 24 detects the intensities ofthe emitted fluorescence at a wavelength different from that of theincident radiation. The detected emitted radiation may be analyzed byknown methods. For an automated system, a controller 32 controls theoperations of the CE system 200.

Multiple Capillary Cartridge Based CE System

FIG. 2 shows an overall perspective view of the CE system 200 (e.g., anDNA Analyzer). The CE system 200 incorporates an interface mechanism 300(only rear support block 363 is shown in FIG. 2, otherwise schematicallyand generally represented as a dotted line structure in FIG. 2 to notobscure the cartridge 100), in accordance with one embodiment of thepresent invention. The interface mechanism 300 supports a multi-channelcartridge 100 in accordance with the one embodiment of the presentinvention, which provides easy handling of multi-channel separationcolumns, and allows easy optical coupling of the detection zones to thedetection optics of the CE system 200. Details of the interfacemechanism 300 will be described below. The fully automated DNA analysissystem 200 has a base 74, supporting a modular X-Z sample handling traymechanism 80, which moves one 96-well micro-titer plates 70 and a bufferplate 72 in relation to the multi-capillary cartridge 100 supported bythe interface mechanism 300. The system 200 provides easy handling ofmulti-channel separation columns, and allows easy optical coupling ofthe detection zones to the detection optics of the CE system 200. Theoperations of the CE system 200, including the interface mechanism 300,is controlled by a controller 32.

In accordance with one embodiment of the present invention, the blockdiagram of the controller 32 for the CE system 200 is shown in FIG. 3.The controller comprises a processor as part of the A/D Board (LEDProcessor) 912 with CPU 910 for converting detection signals receivedfrom the PMT 178 (FIG. 13) to corresponding digital signals, coming fromLEDScan PCBA interface 914 for transferring and receiving signals to andfrom respective parts of the CE system 200 by instructions from the CPU910. The A/D (LED Processor PCBA) interface 912 is coupled to thevarious actuators in the interface mechanism 300 to control and connect(using the interface mechanism 300) at least high voltage power supply76, pneumatics 78, motor controls (X-Z sample/buffer tray) 80 andinterlocks (cartridge and transport doors) 61 and 62. The A/D or LEDProcessor PCBA 912 also controls the high-voltage power supply 76 forsample injection and electrophoresis functions of the CE system 200, acircuit 914 (LEDScan Board) for modulating the excitation radiationsource (e.g., LEDs) 921 and the PMT detector module 178, of the CEsystem 200. The A/D (LED Processor PCBA) 912 may be further coupled toan external personal computer 918, which in turn performs dataprocessing or additional control function for the CE system 200 usingBioCal's BioCalculator Software to control various features andfunctions of the automated multi-channel DNA analyzer 200.

The components of the controller 32, with the exception of the PC 218,may be packaged as an electronic board 64 (FIG. 2) and cooling fans 62,on board the CE system 200 and electrically coupled to the PC 218 via aserial port (not shown), or they may be part of a separate controllermodule outside of the CE system 200. The CPU 210 and/or the PC 218 areprogrammed to accomplish the various control functions and features forthe CE system 200. In one embodiment, the PC 218 can be configured toprovide the user control interface for the CE system 200 (e.g., userinitiation of the connection sequence of the interface mechanism 300).It would be within a person skilled in the art to implement the programcode given the functions and features disclosed herein. In an alternateembodiment, the controller 32 or components thereof may be incorporatedas part of the PC 218.

Capillary Cartridge

The multi-channel capillary cartridge 200 includes twelve detectionzones 155 (See FIG. 8, which is also schematically represented as 30 inFIG. 1), defined by capillaries 140 held in a cartridge body. Thecartridge 100 includes a twelve-channel fused silica capillary arraythat is used for separation and detection of the samples as part of adisposable and/or portable, interchangeable cartridge assembly 100. Thecartridge 100 shown in FIG. 2 holds up to 12 capillaries 140, 12-18 cmlong. The cartridge 100 is integrated with a top, outlet bufferreservoir 130 common to all capillaries 140, which is directly coupledby the interface mechanism 300 to a modular compressed gas source 78,such as a replaceable pressurized gas cartridge of an inert, compatibleor non-reactive gas (e.g., Nitrogen, CO₂, etc.) or a pressure pump.Appropriate pressure plumbing, including tubing, pressure valve andsolenoid controls, is provided. (Details of such plumbing are omitted,since it is well within one skilled in the art to configure suchplumbing given the disclosure herein of the functions, features andoperations of the system 200.) The pressure source 78 provides therequired gas pressure to fill-up all the 12-capillaries with the sievinggel contained in the reservoir 130 and to purge the gel from theprevious run from the capillaries during the refilling process.Depending on the viscosity of the gel, pressures of up to 40 PSI may beapplied to the capillaries 140 through the gel-filled reservoir 130. Thecartridge gel-reservoir 130 is equipped with a built in common electrodeanode 134 (see FIGS. 7 and 8) for all 12-capillaries, which isautomatically connected by the interface mechanism 300 to a high voltagepower supply 76 (FIG. 2) for electrophoresis when installed inside thesystem 200. A fan or Peltier cooler on the adjacent structure to thecartridge 100 provides temperature control of the cartridge. Thecartridge will have vent holes (input and output) for air circulation(temperature controlled air to be introduced to the cartridge from theinstrument side). A power supply 66 (FIG. 2) provides DC power to the CEsystem 200.

FIGS. 4-16 illustrate in detail the assembly of the components for thecartridge (the covers 146 and 148 at the mid-section 120 is omitted fromview, to show the internal components). They are described here forillustrative purposes and are not to be taken in a limiting sense. FIG.4 shows the lower-section body 110 of the cartridge 100. At the upperend of the lower-section body 110 are openings 126 through whichportions of the excitation fibers 116 are placed; after being placedthrough these openings, the excitation fibers 116 are bonded in place.(Other means of securing these components may be used as well.) At thelower end of the lower-section body 110 are cathode electrodes 114 thatare also bonded to the lower section 110 (or insert molded as part ofthe lower section 110). The capillaries 140 (FIG. 7) are insertedthrough holes 137 and guided to these cathode electrodes 114. Ports 343provides external access to the cathodes 114 by cathode contacts 342described in connection with the interface mechanism 300 below. For atwelve-capillary cartridge, there are twice as many excitation fibers(i.e., twenty-four excitation fibers), in case of upgrading fordual-wavelength type detections. These excitation fibers 116 arepositioned to alternate around the twelve capillaries 140. This is seenmore clearly as fiber openings 126 a and 126 b may be used forexcitation fibers 1116 a and 116 b (FIG. 4) for capillary 140,respectively.

FIG. 5 shows the addition of the cartridge mid-section body 120 to thelower-section body 110 in FIG. 4. The cartridge mid-section body 120 isdesigned so that the part 132 does not obstruct the path of theexcitation fibers 116 or that of the capillaries 140. The part 132 hascutouts that provide clearance to or do not enclose the excitationfibers 116. This part 132 also has holes 138 through which thecapillaries 140 are placed, as will be shown in further figures. The topend 131 of the mid-section body 120, which will form part of thereservoir, also has holes 139 through which the capillaries 140 will beplaced.

After the mid-section body 120 of the cartridge is mounted onto thelower-section body 110, as shown in FIG. 6, polyimide coated capillaries140 are placed through the capillary holes 137, 138 and 139 until theyreach the lower end of the lower-section body 110 (see FIG. 7). Thecapillaries 140 have a pre-burned window, with the polyimide coatingremoved to provide a detection window. Staples 136 may be used to securethe capillaries 140 to the mid-section body 120 of the cartridge. (Othermeans of securing these components such as o-rings may be used as well.)At the top end 131 of the mid-section body 120 is a common anodeelectrode 134 for the capillaries that extends into the reservoir.

FIG. 8 shows the cartridge with the combined mid-section andlower-section bodies 110 and 120, respectively. The capillaries extendfrom the top of the mid-section body 120 (with the capillary tips 141protruding at the opening 131 for the reservoir) to the bottom of thelower-section body 110 with the cathodes 114. The detection zone 155 ofthe capillaries is also shown. The excitation fibers 116 are shownthrough fiber openings 126 (see also FIG. 4) up to the V-groove blockassembly 150, where light from the excitation fibers is directed at thecapillaries.

In FIG. 9, a rear view of the cartridge is shown. The cartridge isintegrated with a top/outlet buffer reservoir 130 common to allcapillaries. The gel reservoir 130 is attached to the mid-section body120 with an O-ring 144 as a seal. The gel reservoir 130 has a capacityof about 18 cc and may have transparent, or clear, windows on each sidefor inspection of the gel level. The cartridge 100 has a single commonanode 134 at the top opening of the mid-section body 120 and multiplecathodes 114 at the lower-section body 110 as part of the cartridgeassembly. (Other means of having two separate electrodes may be used aswell.) The cartridge gel reservoir 140 is equipped with a built-in anode134 common for all twelve capillaries, which is automatically connectedto the high voltage power supply 76 via anode contact pins 304 providedon the interface mechanism in the interface module 300, forelectrophoresis when installed inside the CE system 200, as will bedescribed below. A commercially available high voltage power supply(i.e. Emco) is used to deliver 0 to 20 KV of electrical field togel-filled capillaries 140 for the electrokinetic injection andseparations of DNA fragments.

The reservoir 130 containing the gel is sealed, such as hermeticallysealed at the body of the cartridge, which allows the cartridge to behandled by holding it in an orientation without leakage of the gel.(There is negligible leakage or exposure at the capillary tips becauseof surface tension and high viscosity within the microbore of thecapillaries.) The cartridge 100 has a purge hole 77 that is coupled topurge-air barrel 303 from the instrument (see FIG. 18) that providescompressed gas from the pressure source 78 into the cartridge reservoir130. This allows pressurized gas to fill the capillaries with thegel/buffer solution before each separation run, and to purge the old gelfrom the previous run in the process. This approach assures the propercontainment of the gel inside the cartridge reservoir; it also providesa simple and reliable means of accessing the gel reservoir and ofproviding enough gas pressure for the gel to fill up the capillariesprior to applying high voltage to effect CE separation. Depending on theviscosity of the gel, pressures of up to 40 PSI have been applied to thecapillaries through the gel-filled reservoir. As will be describedbelow, the interface of the gas pressure to the reservoir 130 isprovided by the interface mechanism 300, via the pressure port (hole) 77provided on the reservoir 130.

The cartridge 100 also has detection optic ports 161 through whichdetector probes 170 (FIG. 11) are fitted. Through each of thesedetection optic ports 161, micro-lenses 166 for emission collectionoptics are placed, followed by elastomer lens retainers 168. Thecartridge also has a shutter covering, or a multi-channel aperture strip142, at the detection optic port 161. The aperture strip 142 may be athin Polyester material about 0.5 mm thick, which will prevent any dustparticles or foreign objects from entering inside the collection opticsarea. The apertures 142 will open up when the detection probes 170containing the collection optics enter the cartridge. The apertures 142will close up again when the detection probes 170 are removed from thecartridge assembly. The shutter can also be a mechanical covering orwindow, which opens up when it is interfaced with the instrument'sdetection optics.

The last stage of assembling the cartridge is shown in FIG. 10 with thefront cover 146 and the rear cover 148. The rear cover 148 has holesdefining each of the detection optic ports 161. There are also ventholes 165 above holes 162 through which cooled air flows inside thecartridge to cool the capillaries.

FIGS. 11 and 12 show the rear view 124 of the cartridge 100 with aclearer view of the emission detector probes 170. FIG. 12 shows that thelower-section body 110 is symmetrical, front and rear (i.e., seemirrored LEDs 184 a and 184 b). FIG. 13 shows a perspective sectionalview of the cartridge 100 with a detector probe 170 coupled to a singlephoto-multiplier tube (PMT) 178 through a fiber connector 174 and anemission filter 176.

FIG. 14 shows a sectional view of the cartridge 100 along with theexcitation and emission optical systems. The cartridge 100 is supportedby a support frame 164 (see also FIGS. 22 and 26) found in the interfacemechanism 300. The cartridge when installed inside the instrumentthrough this support frame 164 in the interface mechanism 300 getsmechanically aligned with LED module/barrel assemblies. The structure ofthe lower body of cartridge 110 provides the optical alignment means orcoupling of lens barrel assembly 188 to the excitation fibers inside thecartridge. The excitation system includes the coupling micro-ball lenses182 with respective LEDs 184. The excitation light from the LEDs 184 isdirected through the excitation fibers 116 to the detection zone 155 ofthe capillaries. The emission system includes the emission collectionfiber array 170, which is connected at the rear side 122 of thecartridge 100.

FIGS. 19A and 19B shows the external structure of a cartridge 101 inaccordance with another embodiment of the present invention. Thefunctional features and structures of this embodiment of the cartridge101 are quite similar to those of the cartridge 100 described in theprevious embodiment.

Excitation System

FIG. 15 is shows in greater detail section A in FIG. 14. A perspectivesectional view of the cartridge section A is shown in FIG. 13. Theexcitation system is supported by the excite support frame 164, which isfitted to the cartridge (in FIG. 10) during use (as shown in FIG. 11).Since the excitation fiber 116 must receive light and direct light alongits path toward the capillary detection zone 155, the excitation systemis configured to allow the required light to enter excitation fiber 116through a ball lens 182 from LED 184. The excitation system includesball lens 182, LED 184, and elastomer spring 190, which are all arrangedwithin lens barrel 188. A piston 191 supports the lens barrel 188. Thepiston is supported by and free to move axially against a coil spring192 on the support frame 164. A retainer 194 is provided at the end ofpiston 191. LED lead 196 is threaded through piston 191. Within the lensbarrel 188, the elastomer spring biases LED 184 against ball lens 182.The coil spring 192, which rests on the excite support frame 164,provides axial and angular compliance in the lens barrel 188, thusallowing ball lens 182 to center accurately in conical lens seat 186.Both these biasing forces provide a closer contacting path for theexcitation light to travel, from the LED 184 through the ball lens 182to the excitation fiber 116.

Two excitation fibers 116 for two wavelengths (for each capillary) areintegrated inside the cartridge 100, with fixed alignment, at closeproximity to the capillary detection zone 155. These two excitationfibers 116 are coupled to two LEDs 184 (e.g., two different colors: 526nm and 473 nm) when the cartridge is installed inside the CE system 200(i.e., DNA Analyzer). Two colors can be separated and detected bytwo-color emission filters at the detection module (PMT module 178). Thecartridge 100 can have single color capabilities for DNA fragmentanalysis applications and also can be upgraded to have two-colordetecting capabilities for other applications.

Detection System

U.S. patent application Ser. No. 10/060,052, which had been fullyincorporated by reference herein, is more specifically directed to thetime staggered/multiplexed detection scheme that can be adopted in theCE system 200 in which the cartridge 100 is designed to be used.

FIG. 16 shows in greater detail the detection, or emission, section B inFIG. 13. Excitation light from a light source (e.g., LED 184) travels inthe excitation fiber 116 to the detection zone 155 of the capillary 140.A fiber ferrule 210 strengthens and protects the excitation fiber 116that is inserted within V-groove block 150. Two excitation fibers 116may be guided to one V-groove block 150, both directing light from thetwo lower angle openings of the V-groove block. (U.S. patent applicationSer. No. 10/319,803 discloses in greater detail additional embodimentsof detection optics to the capillary.) The preferred embodiment foraligning each excitation fiber with a capillary is a single blockfeaturing machined V-grooves that nest both the capillary and the fiberin precise alignment to each other. The block may be manufactured byusing tooling for a coined part or by injection molding. Also, a crossdrilled screw machine part may be used in which the capillary and fiberswould be loaded in precisely machined holes rather than in V-grooves.

When the excitation light is directed at the detection zone 155 (alsosee FIG. 17), the detection system detects emitted light, or emissionsignals at 90 degrees with respect to the excitation plane. Collimationoptics for collimating the emission beam is needed since the emissionfiber 180 is outside the liquid or gel. The Numerical Aperture of theexcitation fiber 116 determines the amount of power density launchedinside the gel close to the detection zone. The excitation light sourcemay be a LED 184, which is relatively inexpensive, or a laser (may be asolid state laser, gas laser, dye laser or the like). The florescenceemissions from the separated components or analytes at the detectionzone is collected through micro-lenses 166 and 167, and directed throughan emission collection fiber 180 to a detector. The fiber 180 is held inplace by a ferrule 208 in the detector probe 170. As will be describedbelow, the detector probe 170 is actuated by the interface mechanism300. Between these two ball lenses 166 and 167 is a spacer 206.Alternatively, a single ball-lens coupling may be adopted. The capillary140 may have transparent walls, or opaque walls provided with atransparent window to direct emissions to the micro-lenses 166 and 167(or alternatively using a single micro-ball lens 166). The lens 166 isused for collecting emissions and preferably has a high collection angleproperty (e.g., a sapphire micro-lens with index of refraction of n=1.76from Swiss Jewel Company Model # B2.00 that has a short focal distancewith a high numerical aperture (N.A.)). The lens 167 is for coupling thecollimated emission light produced by the sapphire lens to the emissionfiber 180 (e.g., a BK-7 micro-lens, available from the Swiss Jewel Co.).The fluorescent light, which has a higher wavelength (e.g., 570 to 630nm) than the excitation light, is then routed by a large core opticalfiber 180 (370 μm O.D., 0.22 NA fibers, but could also be in ranges of:100-1000 μm O.D., 0.12-0.5 NA) to the detector 178 (e.g., RS984Hamamatsu photo-multiplier tube (PMT)) after going through colorseparation (e.g., using 570-630 nm) long pass emission filters. Theemission signals are relayed by emission fibers 180 into the detectormodule 178, where they are filtered by a single or multiple emissionfilter 176 and are read (detected) in a time-multiplexed(time-staggered) scheme. The detection fiber 180 can be seen moreclearly in connection with the detection optics system as described andshown in FIG. 13.

Interface Mechanism

The interface mechanism of the present invention accomplishes quick andreliable interface connections to the disposable gel contained capillarycartridge 100. These interface connections include an gas pressurizationconnection, high voltage connections, and precision optical connections.The interface also provides precise and repeatable mechanicalpositioning of the cartridge, to accurately position the components ofthe cartridge in relation to the support elements in the CE system 200,including positioning the capillary tips in relation to external sampleor buffer reservoirs, found on 96-well titer plate, for example.Additionally, the interface provides separate electrical and opticalconnections to each separation channel, thus providingchannel-to-channel isolation from cross talk both electrically andoptically and insulation to the rest of the instrument from highvoltage.

One aspect of the present invention provides an interface mechanism thatprecisely positions the cartridge in relation to the support elements(e.g., high-voltage, pressurize gas, incident radiation and detector)provided by the supporting instrument, and makes automated, reliable andsecured alignments and connections between various components in thecartridge and the support elements in the instrument. Such alignmentsand connections are reliably implemented, in a reliable automatedsequence, after the cartridge had been securely received by theinterface mechanism.

In another aspect of the present invention, the interface mechanismcomprises pneumatically or electro-mechanically driven actuators forengaging structures on the cartridge, to securely connect at least oneof gas pressure, high voltage, emission detection optics, and excitationradiation optics. In one embodiment, the pneumatically driven actuatorscomprise gas driven pistons.

In a further aspect of the present invention, the interface providesseparate high voltage and optical connections for each separationchannel in the cartridge, thus providing channel-to-channel isolationfrom cross talk both electrically and optically.

FIG. 18 provides an overview of the relationship of various cartridgecomponents and the functional components of the interface. In thisembodiment, all mechanical actuations are pneumatically driven, an inparticular, gas driven by the pressure source 78 (FIG. 2) viaappropriate pressure hoses and solenoid control valves, which may bepart of the various pneumatic actuators. Pneumatically driven actuatorsare easier to be integrated into the interface mechanism due to thepresence of high voltage lines feeding high voltage current to thecartridge. Electro-mechanical, manual-mechanical, and other actuationsare also possible as an alternative, without departing from the scopeand spirit of the present invention.

As shown in FIG. 18, the interface mechanism comprises the followingactive elements that align and engage to associated components in thecartridge:

(a) Purge-air piston barrel 303 provides pressurized gas (e.g., N2) tothe cartridge reservoir 130 by o-ring coupling of the purge-air barrel303 to the reservoir purge hole 77. The purge-air barrel 303 comprisespiston that is pneumatically driven.

(b) High voltage anode contacts 304 and barrels 305—Two axiallycompliant contacts 304 provide high voltage connections to the commonanode 134 through anode contact ports 306. The contacts 304 are in theform of spring loaded pogo pins each mounted in pneumatically drivenpiston barrels 305.

(c) Locator piston barrels 309—Two pneumatically driven piston barrels309 pushes against the cartridge 100, such that the conical noses 307mate with conical seats 310 in the cartridge mid-section 120 toprecisely position the cartridge 100 in relation to the interfacemechanism 300 and the CE system 200.

(d) Excitation source (LED) barrels 188: Twelve barrels 188 (ortwenty-four barrels, in the case of two excitation wavelengths perchannel), each housing a ball lens 182 coupled directly to an LED 184within the barrel, are mounted vertically on springs 192 (shown in FIG.15) in the interface mechanism 300. The springs 192 provide the axialcompliance required for passively aligning the ball lenses 182 to matingconical seats 186 in the cartridge lower-section 110, thereby effectingtwelve independent excitation optical couplings to the cartridge 100.Radial compliance for each barrel is accomplished by a mounting designthat allows angular deflection (Lens Seat 186) of the barrels 188 as theball lenses 182 enter the conical seats 186 in the cartridgelower-section 110. The LEDs 184 are all spring loaded with elastomersprings 190 in the barrel 188, which provides independently compliantforces to each lens barrel assembly 188 for a reliable and repeatablealignment to the excitation fiber 116 in the cartridge 100. Thecartridge has all the proper conical type features (i.e., conical lensseating 186) to accept the elastomeric spring loaded LEDs 184 from theCE system 200. In another embodiment not shown, the LED source barrel188 may be actuated by actuators such as the pneumatic actuators for theother barrels described herein.

(e) Emission detection probes 170 and piston barrels 320—The cartridge100 has alignment features to be easily aligned to the micro-opticaldetection module inside the system 200. Twelve probes 170 each housing aball lens 166 coupled to an optical fiber 180 (see FIGS. 16 and 17) aresupported on a frame 371 (see FIGS. 20, 22, 26) that is mechanicallydriven by a pair of pneumatically driven piston barrels 320 that providethe parallel actuations of the probes 170 for interfacing the detectionports 160 in the cartridge 100. In one embodiment, the ball lens 166 atthe tip of each probe 170 mates to a conical seat at each capillary 140in the cartridge 100. Each probe 170 is independently compliant bothaxially and radially, such as by providing an elastomer spring as in thecase of the excitation source barrels 188. The distal end of each fiberis coupled to the PMT assembly 178.

(f) Cathode contacts 340 and barrels 342—Similar to the high voltageanode contacts 304, 12 axially compliant contacts 340 provideconnections to the twelve cathodes 114 in the cartridge 100 through thecathode contact ports 343. The cathode contacts 340 are each in the formof a spring-loaded pogo pin mounted in a piston barrel 342. All twelvepiston barrels are mechanically supported on a frame 373 (see FIGS. 20,22, 26) that is driven by a pair of pneumatically driven pistons 344(schematically shown) that provide parallel actuations of the barrels342 for interfacing to the cathodes 114 in the cartridge 100.

FIGS. 20-32 are perspective design drawings showing the actual structureof the interface mechanism 300 in accordance with one embodiment of thepresent invention. The interface mechanism 300 generally comprises afront support block 360 and a rear support block 363. The relevantcomponents described above are shown in the figures using like referencenumerals. It is noted that in these figures, the sample/buffer wells 70and 72 are schematically represented in the form of vials.

FIGS. 20 and 21 is a rear perspective view of the interface mechanism.In this embodiment, a cooling duct 365 is provided in the rear supportblock 363 to provide cooling air to the capillaries 140 in thecartridge, via vent holes 165 on the cartridge 100 (shown in FIGS. 10and 12). Referring also to FIG. 31, the duct 365 expands into a plenum367 that covers the vent holes 165 on the cartridge 100. The duct 365 isconnected to an external duct coupled to a suitable cooling air pump orfan (not shown). Leads 370 extend from the LED source barrels 188. Aconnector module 179 is provided on the rear support block 363, forhousing the collimating microlens array, and coupling to optic fibers180 to the detection probes 170.

FIGS. 22A and 22B are front perspective views of the interface mechanism300. A gas manifold 177 is provided on the front support block 360 ofthe interface mechanism 300, to couple and distribute pressurized gas tothe actuators disclosed above. The plumbing includes tubings that arenot shown in the figures.

FIG. 23 is a front view of the interface mechanism. FIG. 24 is a rearview of the interface mechanism 300. FIG. 25 is a side view of theinterface mechanism 300. FIG. 26 is a side sectional view of theinterface mechanism 300, taken along line 26-26 in FIG. 28. FIG. 27 is abottom view of the interface mechanism 300. FIG. 28 is a partial topview and top sectional of the interface mechanism 300, taken alone line28-28 in FIG. 23, to show the top and bottom halves of the interfacemechanism 300. The various views provide additional details to thestructure of the interface mechanism 300.

The front and rear support blocks 360 and 363 of the interface mechanism300 are provided with holes to receive the various barrels and/oractuators described above. The positions of the holes match theassociated components on the cartridge 100.

FIG. 29 is a rear view of the front support block 360 of the interfacemechanism 300. FIG. 30 is a front view of the front support block 360 ofthe interface mechanism 300. FIG. 31 is a front view of the rear supportblock 363 of the interface mechanism 300. FIG. 32 is a rear view of therear support block 363 of the interface mechanism 300. Beveled surfaces381 and 382 are provided on the rear support block 363 and beveledsurfaces 383 and 384 are provided on the front support block 364 toreceive the beveled edges 391 and 392 (combined in the form of aV-shaped side edge) on either side of the cartridge 100, as best seenfrom the view in FIGS. 28 and 19A). The assembly of the support blocks360 and 363 would be evident from the various drawings provided herein.

Operation of Interface Mechanism

With the interface mechanism of the present invention, the operation ofthe instrument becomes simpler, more reliable, and repeatable. Thecartridge with self-contained, pre-aligned optics with respect to theseparation channels, can be easily received into the CE system 200 in apositive, secured manner, allowing for improved alignment to externalcomponents in the CE system 200, and secure reliable connections ofsupport elements to be made in an automated sequence.

The cartridge 100 is manually placed vertically into the opening at thetop of the interface mechanism 300. Optionally, a hinged door or safetylatch 350 (shown in 26) that covers the top of the cartridge 100 isprovided in the interface mechanism 300. This safety latch iselectrically interlocked 61 (FIG. 3) to the interface mechanism 300 byan interlock switch to prevent accidental removal of the cartridge 100,thereby avoiding hazardous conditions. The cartridge 100 comes to reston the spring-loaded excitation source (LED) barrels 188 in theirhighest position. If a safety latch is provided, the operator manuallycloses the door thereby activating the interlock switch. Alternatively,instead of a latch covering the top of the cartridge, an interlockingsafety latch is provided in the interface mechanism 300 that latch ontoa complementary structure on the cartridge.

After the cartridge has been securely received by the interfacemechanism 300, a connection or interfacing sequence is initiated by theBioCalculator (user interface) software from computer 918. In oneembodiment, the interfacing sequence is manually initiated by anoperator from the operator's control screen (e.g., on the PC 918). Anindicia may be displayed in the user interface on the control screen,indicating that the cartridge 100 is securely seated in the interfacingmechanism 300. Alternatively, the interfacing sequence may be initiatedautomatically in response to a secured reception of the cartridge to theinterface mechanism (e.g., by the feedback signal of a sensor).

Upon initiation of the interfacing sequence, the following sequence isexecuted automatically, in accordance with one embodiment of the presentinvention. The tips 307 of the locator pins 308 are actuated by thelocator barrels 309 to engage the locator seats 310 on the cartridge100, thereby precisely positioning the cartridge 100 into a finalaligned position in relation to the interfacing mechanism 300 forsubsequent engagements by the remaining interface barrels. A secondaryaffect of this positioning is the final seating of the excitation source(LED) barrels 188. The status of the secured engagements of the locatorbarrels 309 against the locator seats 310 may be displayed on theoperator control screen.

The other piston barrels may engage the cartridge 100 together, or in apredetermined sequence. This stage may include the following:

(a) The purge-air piston barrel 303 gets actuated to engage thecartridge reservoir 130.

(b) High voltage anode contact barrels 305 actuate the anode contacts304 to make engagement with the cartridge anode 134 through the anodecontact ports 306.

(c) The emission detection probe piston barrels 320 (schematicallyshown) actuates the detection probes 170 to make engagements with theconical seat at each capillary.

(d) The cathode contact piston barrels 342 actuates the cathode contacts340 to make engagement with the cathodes 114 in the cartridge throughthe cathode contact ports 343.

The interfacing of the support elements to the associated components ofthe cartridge has been completed. The sequence of the engagement of thevarious interfaces may differ from the embodiment described above,without departing from the scope and spirit of the present invention.Several of the interfaces may be grouped and actuated together.

A disconnection sequence is provided to disconnect the support elementsfrom the cartridge, allowing the cartridge to be safely removed from theinterfacing mechanism 300 in the CE system 200. Disengagement of thecartridge is manually initiated by the operator from the control screenand follows a sequence that is essentially the reverse of the abovesequence.

Operation of CE System

Injection of the samples is achieved by electrokinetic methods. The highvoltage power supply 76 is used to deliver 0-to-20 KV of electricalfield to the gel-filled capillaries for the electrokinetic injection andseparations of DNA fragments. Each of the 12-LED's broad band lightenergy (FWHM=47 nm) is relayed by individual light transmitting opticalfibers (multi-mode silica or plastic 200 micron Core fibers, 0.22 N.A.)to each of the capillary's detection zone inside the cartridge 100 forthe excitation of the separated DNA fragments.

In operation, the sample handling tray transport mechanism 80, with a96-well plate (8×12) 70 and 72, is used to introduce the amplified DNAsamples (or analytes) to each capillary 140. The X-Z transport mechanism80 indexes a row of sample carrying wells under the row of capillarytips and dip the tips into the well. By applying a voltage,electrokinetic injection moves a known amount of the DNA sample to thebeginning of the separation column 140. After injection, the DNA samplesfrom sample tray 72 may be replaced with a running buffer from tray 70.Alternatively, after injection, the transport mechanism 80 may index tomove a row of 12 wells containing buffer solution into position underthe cartridge to replace the twelve wells containing DNA samples. Byapplying high voltage across the total length of the capillary 140,separation of the DNA sample into DNA fragments is achieved. As thefragments approach the end of the capillaries 140 and enter into thedetection zone 155, the excitation light energy from each of the twelveLEDs 184 is delivered by the light transmitting optical fibers 116 fromoutside the detection window, illuminating the migrating DNA fragmentsfrom sample tray 72. As the twelve (or twenty-four in the case of dualwavelength detection) LEDs 184 are time-multiplexed (with samplingfrequency of 1-100 Hz), twelve emission signals coupled to twelveemission detection fibers 180 will reach the single PMT 178 in atime-staggered manner by a 12-fiber bundle assembly (see U.S.application Ser. No. 10/060,052).

To prepare for the next run with a different sample, the old gel fromthe previous run is purged from the capillaries by pressuring thereservoir to refill the capillaries with fresh gel. The trays 70 and 72carries cleaning solutions, waste collection, and samples. The purgedgel is collected by one of the trays 70 and 72 by positioning the tipsof the capillaries at a row of waste collecting wells in one of thetrays. The tips of the capillaries may be cleaned with water or acleaning solution by positioning and dipping the tips of the capillariesin such solution in the appropriate tray wells. When the capillaries arerefilled and ready for the next run, the tips of the capillary aredipped into the samples by repositioning the tray 70 or 72. The abovementioned sequence of process may be programmed as one of the automatedfunctions of the controller 32. The interface mechanism 300 provides theinterfacing of support elements in the CE system 200 to the cartridge,such as high voltage, gas pressure, LED radiation source, and detectionoptics, as described above.

While the invention has been particularly shown and described withreference to the preferred embodiments, it will be understood by thoseskilled in the art that various changes in form and detail may be madewithout departing from the spirit, scope, and teaching of the invention.Interface mechanisms including the concept of the present invention maybe adapted to receive capillary cartridges of other structural designs.A person skilled in the art will recognize that the instrumentincorporating the essence of this invention can also be used forbimolecular analysis other than DNA analysis. For example, by alteringthe separation gel or buffer, the instrument can also be modified toanalyze biomolecules like proteins, carbohydrates, and lipids.

By way of example and not limitation, the detection scheme of thepresent invention is described in connection with capillaryelectrophoresis and radiation induced fluorescence detection. It isunderstood that the present invention is also applicable to detection ofanalytes separated based on bio-separation phenomenon other thanelectrophoresis, and detection of radiation emissions other thanfluorescence emissions, including other types of emissive radiation,such as phosphorescence, luminescence and chemiluminescence, as well asabsorbance based detection.

Furthermore, while the separation channels in the described embodimentsare defined by cylindrical columns or tubes, it is understood that theconcepts of the present invention is equally applicable to separationchannels defined by channels, for example micro-channels (such assquare, rectangular or essentially semicircular cross sections) definedby etching in a substrate (micro-fluidics type devices or bio-chips).

The transport mechanism can be configured to move the trays in ahorizontal plane, and an additional transport mechanism may be providedto move the cartridge vertically to access the trays.

Accordingly, the disclosed invention is to be considered merely asillustrative and limited in scope only as specified in the appendedclaims.

1. An interface mechanism for interfacing at least an associatedcomponent of a capillary cartridge to at least an external componentthat provides to the associated component of the capillary cartridge asupport element required by a bio-analytical process for a bio-sample,comprising: a support structure supporting the cartridge in relation tothe external component, wherein the support structure comprises alocation device and an actuator that biases the location device againstthe capillary cartridge to positively position the capillary cartridgein relation to the external component; at least one biasing devicesupported by the support structure, the biasing device supporting andbiasing the external component against the associated component of thecapillary cartridge, thereby providing the support element to thecartridge to conduct the bio-analytical process; and a controllercontrolling operation of the biasing device and the location device,wherein the controller is configured to activate the location device topositively position the capillary cartridge prior to activating thebiasing device to bias the external component against the associatedcomponent of the capillary cartridge.
 2. The interface mechanism as inclaim 1, wherein the biasing device comprises a compliant membersupporting and biasing the external component against the associatedcomponent of the capillary cartridge when the capillary cartridge issupported by the support structure.
 3. The interface mechanism as inclaim 2, wherein the external component provides incident radiation. 4.The interface mechanism as in claim 1, wherein the biasing devicecomprises an actuator operatively coupled to the external component. 5.The interface mechanism as in claim 4, wherein the actuator comprises atleast one of a pneumatic actuator, a electromechanical actuator, and amechanical actuator.
 6. The interface mechanism as in claim 5, furthercomprising a source of compressed gas operatively coupled to thepneumatic actuator.
 7. The interface mechanism as in claim 1, whereinthe capillary cartridge is interchangeable and removably supported bythe support structure, and wherein the biasing device is structured toremovably bias the external component against the associated componentof the capillary cartridge to provide a quick connection.
 8. Theinterface mechanism as in claim 1, wherein the external component isassociated with a support element comprising at least one of electricalpower, a pressurized gas, incident radiation, detection optics.
 9. Theinterface mechanism as in claim 1, wherein the capillary cartridgecomprises multiple separation channels, and wherein the supportstructure supports the capillary cartridge in relation to a plurality ofexternal components, wherein each external component is associated witha support element, and at least one external component being associatedwith each separation channel.
 10. The interface mechanism as in claim 9,wherein the support element associated with each external componentcomprises at least one of electrical power, a pressurized gas,excitation radiation, detection optics.
 11. The interface mechanism asin claim 9, wherein a plurality of external components are associatedwith each separation channel, the plurality of external components areassociated with a plurality of support elements, including at leastelectrical power, a pressurized gas, incident radiation and detectionoptics for each separation channel.
 12. The interface mechanism as inclaim 9, wherein at least one support element is provided by an externalcomponent that is separate from other external components associatedwith similar support element provided to other separation channels. 13.The interface mechanism as in claim 12, wherein the external componentprovides to the associated component of the capillary cartridge, atleast one of incident radiation, detection optics, and electrical power.14. The interface mechanism as in claim 9, wherein at least one of theplurality of external components is associated with an associatedcomponent of the capillary cartridge which is common to the plurality ofseparation channels.
 15. The interface mechanism as in claim 14, whereinsaid at least one external component provides to the associatedcomponent of the capillary cartridge, at least one of a high voltage anda pressurized gas.
 16. The interface mechanism as in claim 1, whereinthe support structure is provided with a cooling conduit operativelycoupled to the capillary cartridge to direct cooling air to thecapillary cartridge.
 17. A bio-analytical system for conducting abio-analytical process for a bio-sample in a capillary cartridge,comprising: a support for a sample; an interface mechanism forinterfacing the capillary cartridge to a support element required by thebio-analytical process, comprising: at least an external component thatprovides to the capillary cartridge the support element required by thebio-analytical process; a support structure supporting the cartridge inrelation to the external component and the sample, wherein the supportstructure comprises a location device and an actuator that biases thelocation device against the capillary cartridge to positively positionthe capillary cartridge in relation to the external component; at leastone biasing device supported by the support structure, the biasingdevice supporting and biasing the external component against adesignated component of the capillary cartridge, thereby providing thesupport element to the cartridge to conduct the bio-analytical process;and a controller controlling the bio-analytical process in the capillarycartridge, including controlling operation of the interfacing mechanismincluding controlling operation of the biasing device and the locationdevice, wherein the controller is configured to activate the locationdevice to positively position the capillary cartridge prior toactivating the biasing device to bias the external component against theassociated component of the capillary cartridge.
 18. The bio-analyticalsystem as in claim 17, wherein the interface mechanism comprises all theoptics in the system.